Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice

Author(s)

Almeida, Camila Bononi ^[1] ; Scheiermann, Christoph ^[2] ; Jang, Jung-Eun ^{[2, 3, 4]} ; Prophete, Colette ^[2] ; Costa, Fernando Ferreira ^[1] ; Conran, Nicola ^[1] ; Frenette, Paul S. ^{[2, 3, 4]}

Affiliation

^[1] Univ Estadual Campinas, INCTS, Hematol & Hemotherapy Ctr, BR-13083970 Campinas, SP - Brazil

^[2] Albert Einstein Coll Med, Ruth L & David S Gottesman Inst Stem Cell & Regen, Bronx, NY 10461 - USA

^[3] Mt Sinai Sch Med, Dept Med, New York, NY - USA

^[4] Mt Sinai Sch Med, Dept Gene & Cell Med, New York, NY - USA

• Document type: Journal article
• Source: Blood; v. 120, n. 14, p. 2879-2888, OCT 4 2012.
• Web of Science Citations: 38

Abstract

Inhibition of leukocyte adhesion to the vascular endothelium represents a novel and important approach for decreasing sickle cell disease (SCD) vaso-occlusion. Using a humanized SCD-mouse-model of tumor necrosis factor-alpha-induced acute vaso-occlusion, we herein present data demonstrating that short-term administration of either hydroxyurea or the phosphodiesterase 9 (PDE9) inhibitor, BAY73-6691, significantly altered leukocyte recruitment to the microvasculature. Notably, the administration of both agents led to marked improvements in leukocyte rolling and adhesion and decreased heterotypic red blood cell-leukocyte interactions, coupled with prolonged animal survival. Mechanistically, these rheologic benefits were associated with decreased endothelial adhesion molecule expression, as well as diminished leukocyte Mac-1-integrin activation and cyclic guanosine monophosphate (cGMP)-signaling, leading to reduced leukocyte recruitment. Our findings indicate that hydroxyurea has immediate beneficial effects on the microvasculature in acute sickle-cell crises that are independent of the drug's fetal hemoglobin-elevating properties and probably involve the formation of intravascular nitric oxide. In addition, inhibition of PDE9, an enzyme highly expressed in hematopoietic cells, amplified the cGMP-elevating effects of hydroxyurea and may represent a promising and more tissue-specific adjuvant therapy for this disease. (Blood. 2012; 120(14): 2879-2888) (AU)

• FAPESP's process: 11/50959-7 - Standardization of transgenic sickle mice bone marrow transplantation, inflammatory induction and assessment of in vivo platelets role in vaso-occlusion
• Grantee: Camila Bononi de Almeida
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 07/58533-3 - Role of leukocytes in the pathophysiology of sickle cell anemia
• Grantee: Camila Bononi de Almeida
• Support Opportunities: Scholarships in Brazil - Doctorate